More than 100 phytocannabinoids have been isolated to date. See Pertwee, et al. “Hand book of Cannabis,” Oxford University Press, First Edition 2014, ISBN 978-0-19-966268-5. Phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant. These compounds have been investigated based, in part, on their availability from a natural source. The term “cannabinoids” generally refers to not only the chemical substances isolated from C. sativa L exhibiting the typical C21 terpenophilic skeleton, but also to their derivatives and transformation products.
In addition to the historical and anecdotal medicinal use of cannabinoids, the FDA has approved cannabinoid based products, such as Marinol™ and a number of other regulatory agencies have approved Sativex™. Many other cannabinoids are being investigated by the mainstream pharmaceutical industry for various indications. Examples of cannabinoids either approved for clinical use or in clinical trials include Epidiolex™ (e.g., cannabidiol) for Dravet Syndrome and Lennox-Gastaut Syndrome; cannabidivarin for epilepsy; and tetrahydrocannabidivarin for diabetes.
Many different routes to produce cannabinoids and related compounds have been reported. One route involves variations on the Lewis-acid catalyzed Friedel Crafts alkylation of olivetol with menthadienol. For example, U.S. Pat. No. 5,227,537 describes a reaction of equimolar quantities of olivetol and menthadienol in the presence of p-toluenesulfonic acid catalyst which resulted in a 44% yield of cannabidiol after purification by column chromatography. U.S. Pat. No. 7,674,922 describes a similar reaction using a Lewis acid catalyst instead of p-toluenesulfonic acid which results in the formation of significant amounts of the unwanted cannabidiol isomer along with cannabidiol. The reaction route described in the '922 patent resulted in a 47% yield of the desired cannabidiol, a 17.9% yield of the abn cannabidiol and 23% of unreacted olivetol.
In addition, U.S. Pat. No. 3,562,312 describes improved selectivity for the formation of cannabidiol by reacting 6-carbethoxyolivetol with a slight excess of menthadienol in methylene chloride in the presence of dimethylformamide, dineopentylacetal as catalyst. This route resulted in a 42% yield of cannabidiol-carboxylic acid ethyl ester after purification by chromatography.
Another route for the preparation of cannabidiols involves the use of carboxylic acid esters as protecting/directing groups on olivetol analogues. See, e.g., Crombie, L. et al., in J. Chem. Research (S) 114, (M), pp 1301-1345 (1977). In a first step, alkylresorcyl esters (e.g., 6-alkyl-2,4-di-hydroxybenzoic esters) are condensed with unsaturated hydrocarbons, alcohols, ketones, or derivatives thereof such as enol esters, enol ethers and ketals, in high yields to give the corresponding 3-substituted 6-alkyl-2,4-dihydroxybenzoic esters. These routes of preparation have been referred to as acid-catalyzed terpenylation. In a second step, the intermediates with an ester function obtained in the first step are subjected to a decarboxylating hydrolysis, which forms the ester-free cannabinoids.
For example, improvements in selectivity have been achieved by protecting the 4 position of the olivetol related compounds with a carboxylic acid ester. The '922 patent describes the preparation of ethyl cannabidiolate in 82% yield and 93.3% (AUC) purity. After NaOH hydrolysis, however, the route resulted in a 57.5% yield and 99.8% purity (AUC). The '922 patent also describes the need to purify the cannabidiols formed, e.g., Δ-9-tetrahydrocannabinol, by esterification of the free hydroxyl followed by purification of the cannabidiol ester, e.g., Δ-9-tetrahydrocannabinol ester. Purification was performed by crystallization followed by hydrolysis of the ester to the Δ-9-tetrahydrocannabinol. Such steps were required to achieve a purity necessary for pharmaceutical use.
The prior art demonstrates the difficulties of manufacturing cannabidiol compounds or derivatives thereof, e.g., Δ-9-tetrahydrocannabinol, in high yield, high stereospecificity, or both. The causes of these difficulties can include the non-crystalline nature of the materials which renders them difficult or impossible to separate and purify without chromatography. Also, the aromatic portion of the cannabidiol molecule is sensitive to oxidation. And, in one specific example, the thermodynamic stability of the Δ-9-unsaturation relative to Δ-8-unsaturation favors the formation of Δ-8 derivatives.
The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof using a simple synthesis route to produce a cannabidiol compound or derivative thereof in high yield, high stereospecificity, or both.